A mechanistic model for the conformational changes during integrin activation and signaling. (A) Schematic of the domain structure of low-affinity leg-bent CD11b/CD18 (CD11b and CD18 in dark and light gray, respectively). βTD contacts the βA and hybrid domains, and the 2 legs are in close proximity. The αA is occupied by a metal ion in the low-affinity MIDAS (asterisk); the bottom of α7 helix of inactive αA (thick black arrow) is not engaged by βA. (B) Inside-out activation disrupts the βTD contact with βA, which unlocks the βA F/α7 loop and allows the inward shift of the α1 helix leading to the formation of a stable αA-bound βA MIDAS (asterisk), which in turn stabilizes αA in the open (high-affinity) state (open semicircle). (C-D) Ligand (L) (black circle on a stick) bound at αA MIDAS stabilizes the occupancy of βA MIDAS by endogenous αA, opening the βA/hybrid hinge to different degrees (double-headed arrows), with a larger hinge opening forcing genu extension and leg separation (D), resulting in outside-in signaling. See text for additional details.